Research Summary

Using epigenetics to differentiate between two similar neurodevelopmental disorders and identify shared biology

What is the research about?

Genes contain the instructions that determine how our bodies develop, grow and function. Genes are made up of DNA sequences. Changes in our DNA sequence can prevent a gene from working properly. These functionally relevant changes can cause neurodevelopmental disorders. One source of these functionally relevant changes can be caused by “epigenes”. Epigenes are genes that control the expression of other genes by adding epigenetic marks on top of the DNA sequence. These marks direct when and where genes are turned on or off during development. One common epigenetic mark is DNA methylation (DNAm).
In this study researchers investigated two different conditions caused by changes in epigenes.

  1. CHARGE syndrome caused by functionally relevant changes in the CHD7 gene.
  2. Kabuki syndrome caused by functionally relevant changes in the KMT2D gene.
    These two conditions have several features in common, including intellectual disability. They also had some unique features. Researchers found that each condition had a specific pattern of epigenetic (DNAm) marks. This unique pattern is called a ‘signature’.
    Sometimes the significance of a change in a gene is unclear. That is, not all changes in DNA affect the way a gene functions. Researchers used the gene-specific signatures to find which DNA changes affect gene functioning and which ones do not. This is very important as this can help to establish a child’s specific diagnosis.

What did the researchers do?

Researchers analyzed blood samples from healthy control individuals. Samples were also analyzed from people with functionally relevant changes to the CHD7 or KMT2D epigene. DNA from each blood sample received whole genome analysis. The analysis generated DNAm profiles for both groups (Figure 1). Altered DNAm patterns throughout the genome were identified at a specific set of sites specific to each gene. These patterns of DNAm act as unique signatures. These signatures can distinguish between individuals with CHARGE or Kabuki syndrome and controls. Also, these signatures could help with clinical diagnosis. As mentioned above, sometimes gene sequencing can find DNA changes of unclear significance. For example, it is not clear if the change affects gene functioning. Researchers tested the ability of DNAm signatures to answer this question. For example, a child could have a change of uncertain significance in the CHD7 gene. The signature could tell you if the gene function is affected. If this is the case, the child has CHARGE syndrome. If the gene function is not affected the child does not have CHARGE syndrome. More testing would needed to try to establish the child’s diagnosis.

What did the researchers find?

DNAm signatures predicted if a person had DNAm changes more similar to CHARGE syndrome, Kabuki syndrome or to controls. Specifically, it predicted if people had functionally relevant changes in the CHD7 or KMT2D genes.
DNAm signatures associated with changes in the CHD7 and KMT2D genes had similarities. Both signatures had DNAm changes in genes that related to overlapping clinical features in these syndromes. For example, both signatures involved DNAm changes at the HOXA5 gene. This gene is involved in growth and brain development. Individuals with either CHARGE or Kabuki syndrome have neurodevelopmental disorders, including intellectual disability. Syndrome-specific differences are also reflected in the two signatures. The CHD7 signature has DNAm changes in genes related to speech and language difficulties. The KMT2D signature has DNAm changes genes related to hearing loss. Understanding the genes with DNAm changes in each syndrome helps to determine the biological pathways involved in each syndrome’s development. This is an important first step in identifying new treatment targets.

Take Home Message

DNAm signatures have diagnostic value for unclear findings on genetic testing. It helps to determine adiagnosis of CHARGE or Kabuki syndrome. DNAm signatures can predict if an individual with a gene change in either CHD7 or KMT2D has CHARGE or Kabuki syndromes, respectively. This may be especially helpful early in life when clinical distinction between syndromes is more difficult. DNAm analysis can also help us understand the causes of different neurodevelopmental disorders. Understanding these causes can help in determining targets for new treatments. For instance, the shared gene target HOXA5 has similar patterns of DNAm in both signatures. These are distinct from patterns found in controls. HOXA5 is important in neurodevelopment. Changes in gene expression during development could contribute to the overlapping clinical features seen in both syndromes. Thus, a treatment targeting the HOXA5 gene pathway could help people with both syndromes. Analysis of epigenetic mechanisms can provide important insights into the causes of neurodevelopmental disorders. Epigenetics can help to characterize shared and distinct biology underlying the disorders. In the future we expect DNAm signatures to help diagnose and treat a wide variety of neurodevelopmental disorders.


The full research article (CHARGE and Kabuki Syndromes: Gene-Specific DNA Methylation Signatures Identify Epigenetic Mechanisms Linking These Clinically Overlapping Conditions) was written by D.T. Butcher and colleagues, and was published in The American Journal of Human Genetics in May 2017.

For the full article click here.

For the PDF version of the lay summary click here.